Methylenated steroids and process

ABSTRACT

METHYLENATED STEROIDS ARE MANUFACTURED BY REACTION OF THE CORRESPONDING KETO-STEROIDS WITH A METHYLENATING AGENT PREPARED BY THE REACTION OF ZINC WITH A METHYLENE HALIDE IN A SOLVENT SUCH AS TETRAHYDROFURAN OR AN ALKYLENE GLYCOL ETHER OR DIALKOXYALKYL ETHER AND ARE USEFUL AS INTERMEDIATES IN THE MANUFACTURE OF THE CORRESPONDING METHYL DERIVATIVES.

United States Patent US. Cl. 260-3975 12 Claims ABSTRACT OF THEDISCLOSURE Methylenated steroids are manufactured by reaction of thecorresponding keto-steroids with a methylenating agent prepared by thereaction of Zinc with a methylene halide in a solvent such astetrahydrofuran or an alkylene glycol ether or dialkoxyalkyl ether andare useful as intermediates in the manufacture of the correspondingmethyl derivatives.

This application is a continuation-in-part of my copending applicationSer. No. 675,788, filed Oct. 17, 1967, now abandoned.

The present invention is concerned with a novel process for introducinga methylene group into the steroid molecule and with the novelmethylenated derivatives produced thereby. That process involves thereaction of a keto-steroid with the novel reagent prepared by reactionof activated zinc with a methylene halide in a solvent capable ofcomplexing with the halozincmethylene compound produced. Particularlypreferred methylene halides are methylene bromide and methylene iodide.Suitable solvents are tetrahydrofuran, dioxane, alkylene glycol etherssuch as ethylene glycol dimethyl ether and dialkoxy alkyl ethers such asdiethylene glycol dimethyl ether. Tetrahydrofuran and ethylene glycoldimethyl ether are especially preferred. Simple open-chain alkyl etherssuch as diethyl ether are less desirable.

The present process is advantageous over previously known methods forconverting ketones to the corresponding methylene compounds. The Wittigreaction described in Advanced Organic Chemistry, Fieser and Pieser,pages 482-6, Reinhold Publishing Corp., New York (1961) thus suffersfrom a number of disadvantages. As pointed out in that textbook, thetriphenylphosphinemethylene reagent is unstable to air, therefore mustbe prepared in situ. Preparation of the reagent is, furthermore, timeconsuming in view of the fact that several days are required forpreparation of the necessary precursor, i.e. methyl triphenylphosphoniumbromide, from triphenylphosphine and methyl bromide. In addition, theWittig reagent requires more costly raw materials for its preparation.It is noted also that the Wittig reaction is conducted in the presenceof a base, usually phenyl lithium. Such conditions are obviouslyunsuitable for application to steroids with base-sensitive side-chains,e.g. the corticoid side-chain.

The use of an iodomethyl zinc iodide reagent to convert olefins to thecorresponding cyclopropane is described by Simmons and Smith, J. Am.Chem. Soc., 81, 4256 (1959) That reagent is obtained by the reaction ofa zinc-copper couple with methylene iodide and is prepared in situ inthe reaction mixture containing the olefin.

It has been determined that the present reagent is selective in itsaction, depending upon the nature of the ketosteroid starting material.11- and 17-keto steroids, wherein there is not present an adjacentactivating group, are completely unreactive. Unactivated ZO-keto groupsreact very 'ice slowly. Similarly, starting materials containing anapunsaturated keto group and lacking an adjacent activating group areinert. An isolated 3-keto group is, however, quite reactive. Theinsertion of an activating group adjacent to an otherwise unreactiveketo group results in highly reactive starting materials. Especiallyeffective activating groups are those containing an oxygen or nitrogenfunction. Specific examples are the hydroxy and oximino moieties.Starting materials possessing the ketol e (-dOH-) structure are thusespecially suitable for conversion by the instant process. The steroidalketols represented by the following partial structural formulas whereinX is a hydroxy or acetoxy group and Y is hydrogen or a hydroxy oracetoxy group are thus specific examples of preferred starting mterials.Particular species within the scope of those formulas arel7u-hydroXypregn-4-ene-3,20-dione,

17fl-acetoxy-Za-hydroxyester-4-en-3-one,

373,21-dihydroxypregn-5-en-20-one,

2l-hydroxypregn-4-ene-3,ZO-dione,

2l-acetoxy-17a-hydroxypregn-4-ene-3 ,1 1,20-trione,

l7fl-acetoxy-2a-hydroxyandrost-4-en-3-one,

3 fi-benzyloxy-S a-hydroxypregnane-6,20-dione ZO-ethylene ketal,

3 fl,l7fl-diacetoxy-5a-hydroxyandrostan-6-one and 3 ,8,17adiacetoxy-5a-hydroxypregnane-6,20-dione.

The instant novel reagent is prepared by heating activated zinc with theappropriate methylene halide in one of the aforementioned complexingsolvents. Activation of the zinc can be effected, alternatively, byformation of a zine-lead couple or by heating with a hydrogen halide. Aspecific example is the reaction of zinc, activated by heating inmethanol with hydrogen chloride, with methylene bromine intetrahydrofuran to afford the bromozincmethylene tetrahydrofuranreagent, wherein the respective groups are present in the ratio of twobrornine atoms to three zinc atoms to two methylene groups to onetetrahydrofuran molecule. The likely structure is shown below:

The novel process of the present invention is conveniently conducted atroom temperature in a suitable organic solvent such as tetrahydrofuran.A particular application of that process is the reaction of3,8,l7a-diacetoxy 50c hydroxypregnane 6,20 dione with the aforementionedtriszincbismethylene dibromide tetrahydrofuran reagent intetrahydrofuran to afford 3,8,17a-diacetoxy 5a hydroxy 6methylenepregnan 20 one.

The novel methylene steroids of the present invention are particularlyuseful as intermediates in the manufacture of the known and usefulcorresponding methyl compounds. The instant6-methyleneandrostane-3,B,5a,17,8- triol, for example, is oxidized withchromium trioxide to afford 50c hydroxy6-methyleneandrostane-3,17-dione, which is catalytically hydrogenated inthe presence of a palladium catalyst to yield5ot-hydroxy-6a-methylandrostane-3,17-dione. Dehydration of the lattersubstance by reaction with thionyl chloride in pyridine aflords6an1ethylandrost-4-ene-3,17-dione, which is reduced with sodiumborohydride to afford 17/3-hydroxy-6ot-methylandrost-4-en-3-one. Thelatter substance, which is described by Ringold et al., J. Org. Chem.,22, 99 (1959), is both an anabolic and androgenic agent.

The invention will appear more fully from the examples which follow.These examples are set forth by way of illustration only and it will beunderstood that the invention is not to be construed as limited eitherin spirit or in scope by the details contained therein as manymodifications both in materials and methods will be apparent from thisdisclosure to those skilled in the art. In these examples temperaturesare given in degrees centigrade C.). Quantities of materials areexpressed in parts by weight unless otherwise noted.

EXAMPLE 1 Method A.To a refluxing mixture of 64 parts of lead acetateWith 78.8 parts of acetic acid is added rapidly with stirring 26 partsof zinc powder in portions. At that point the heat source is removed,the stirring stopped and the acetic acid removed by suction, leavinggranules of the lead-zinc couple. An additional 78.8 parts of hot aceticacid is then added; the mixture is stirred briefly and the acetic acidis removed by suction. The lead-zinc couple is washed with severalportions of methylene chloride at room temperature, then is dried undera stream of nitrogen at about 125. To the dry material is then added 90parts of tetrahydrofuran and the temperature is lowered to approximatelyAt that time 54 parts of methylene iodide is added with stirring and themixture is cooled for about 10 minutes until cessation of thespontaneous reaction. Stirring is continued at room temperature forabout 1 hour longer, at the end of which time the metallic residue isallowed to settle, leaving an approximately 1 M solution of theiodozincmethylene reagent.

Method B.A mixture of 97.5 parts of zinc dust with 78.8 parts of aceticacid is stirred in a nitrogen atmosphere for about 5 minutes until athick slurry is obtained. At that time 250 parts of water is added andthe resulting mixture is stirred for several minutes. The supernatantaqueous acetic acid is decanted and an additional 250 parts of water isadded. While that slurry is stirred, 37.8 parts of lead acetatetrihydrate is added all at once. Stirring is continued for about minuteslonger, at the end of which time the aqueous supernatant is decanted.The zinclead couple remaining is Washed with another portion of water,then several times with acetone. It is then dried in a nitrogenatmosphere at about 150". To that couple is then added 450 parts of drytetrahydrofuran and 135 parts of methylene iodide is added with stirringat such a rate as to maintain reflux. After the addition is completeheat is applied in order to maintain reflux for about 30 minutes.Cooling of that solution affords a tetrahydrofuran solution of thereagent possessing a concentration of approximately 0.9 M.

A portion of the latter solution is centrifuged to remove suspendedlead, then is cooled to 0. The crystalline solid is isolated bycentrifugation in a nitrogen atmosphere, then is dried at roomtempreature under reduced pressure. It exhibits nuclear magneticresonance peaks at +3 cycles per second (relative to tetramethylsilane),characteristic of the methylene group, and also at 88 and 227 cycles persecond, characteristic of the tetrahydrofuran present as a solvate.Elemental analysis indicates a Zinc content of l5-25%, an iodine contentof 65% and a carbon content of l320%.

4 EXAMPLE 2 To a rapidly stirred mixture of zinc with parts of methanol,under nitrogen, is added 36 parts by volume of an isopropyl alcoholsolution containing 9 parts of hydrogen chloride. The resulting reactionmixture is heated at the reflux temperature for about 5 minutes, at theend of which time the methanol is removed by decantation. The resultingzinc residue is dried at elevated temperature, after which time 135parts of tetrahydrofuran and 58 parts of methylene bromide aresuccessively added. That reaction mixture is heated at the refluxtemperature for about 16 hours, then is cooled to room temperature andan additional 29 part portion of methylene bromide is added. Stirring ofthat reaction mixture at room temperature is continued until all of thezinc has dissolved. At that time the mixture is diluted withapproximately 200 parts of methylene chloride and the resulting whitesolid is filtered in a nitrogen atmosphere under anhydrous conditions.The resulting solid material is washed with small portions of methylenechloride and is dried under reduced pressure at room temperature.Analysis of that reagent indicates the groups to be present in the ratioof three atoms of zinc to two atoms of bromine to two methylene groupsto one molecule of tetrahydrofuran. It exhibits nuclear magneticresonance peaks at about +68, 115 and 225 cycles per second inhexamethylphosphoramide. Its likely structure is shown below:

B r- Z ii EXAMPLE 3 To a solution of 8.3 parts of17B-acetoxy-5a-androstan- 3-one in 45 parts of tetrahydrofuran is added35 parts by volume of the approximately 1 M iodozinicmethylene reagentprepared as described in Example 1. The reaction mixture is allowed tostand at room temperature for about 72 hours, at the end of which time50 parts by volume of 25% aqueous ammonium chloride is added cautiously,and that aqueous mixture-is extracted with ether. The ether extract iswashed successively With aqueous ammonium chloride and aqueous potassiumbicarbonate, then is dried over anhydrous sodium sulfate. Removal of theether by distillation in a nitrogen atmosphere affords the crudeproduct, which is purified by recrystallization from methanol to aflord3-methylen-5a-androstan-17/3-ol 17-acetate, melting at about 98100.Infrared absorption maxima are observed at about 3.25, 5.72, 6.05 and7.95 microns. This compound exhibits nuclear magnetic resonance peaks atabout 280 and 274 cycles per second.

EXAMPLE 4 To a solution of 22.5 parts of l7ochydroxypregn-4-ene-3,20-dione in 22.5 parts of tetrahydrofuran is added 50 parts by volumeof the approximately 1 M iodozincmethylene reagent prepared as describedin Example 1, and the resulting reaction mixture is stirred in anitrogen atmosphere at room temperature for about 15 minutes. Afterstanding at room temperature for about 3 hours, 22.5 parts ofconcentrated ammonium hydroxide isadded with rapid stirring. Nearlysaturated aqueous ammonium chloride in the amount of 50 parts by volumeis then added and the resulting precipitated solids are removed byfiltration. That mixture is then extracted with ether and the etherextract is separated, then washed successively with dilute aqueousammonium chloride and dilute aqueous potassium bicarbonate. The organicsolution is dried over anhydrous sodium sulfate, then concentrated toapproximately 100 parts by volume. The

unreacted starting material which crystallizes at this point is removedby filtration and the filtrate is chromatographed on an alumina column.Elution of that column with benzene-ethyl acetate solutions affords pure17u-hydroxy- 20-methylenepregn-4-en-3-one, melting at about 241- 243".This compound displays an ultraviolet absorption maximum at about 242millirnicrons with a molecular extinction coefficient of about 16,400,infrared absorption peaks at about 2.87, 3.23, 5.99 and 6.20 microns andnuclear magnetic resonance maxima at about 47.5, 70, 77, 290, 293 and345 cycles per second.

EXAMPLE To a solution of 9.3 parts of 3-methoxyestra-1,3,5(10)-triene-16,17-dione 16-monoxime in 45 parts of tetrahydro- Iuran isadded, at approximately in a nitrogen atmosphere, 120 parts by volume ofthe approximately 1 M iodozincmethylene reagent prepared as described inExample 1, and that reaction mixture is allowed to stand at roomtemperature for about 24 hours. The mixture is then stirred rapidlywhile '25 parts by volume of nearly saturated aqueous ammonium chlorideand 26 parts of acetic acid are carefully added. Dilution of thatmixture with approximately 100 parts of water results in precipitationof the solid crude product which is collected by filtration, washed onthe filter with water, and dried, then purified by recrystallizationfrom chloroformmethanol to yield pure 3-methoxy-17-methylenestra-1,3,5(10)-trien-16-one 16-monoxime, melting at about 202- 205 It displays anultraviolet absorption maximum at about 224 millimicrons with amolecular extinction coeflficient of about 17,000 and also infraredabsorption peaks at about 3.05, 5.80 and 6.20 microns.

EXAMPLE 6 To a solution of 17 B-acetoxy-Zot-hydroxyestr-4-en-3-one in 90parts of tetrahydrofuran is added at 15 in a nitrogen atmopsere '36parts by volume of the approximately 1 M iodozincmethylene reagentprepared as described in Example 1. When the mixture becomeshomogeneous, it is allowed to stand at room temperature for about 24hours, then is diluted with nearly saturated aqueous ammonium chloride.The organic solvent is removed by distillation under reduced pressureand the semisolid residue is recrystallized from aqueous methanol.Further purification is effected by chromatography on a silica gelcolumn followed by elution with lbenzeneethyl acetate solutions. Theeluted material is recrystallized from methylene chloride-hexane toafford pure 3-methylenestr- 4-ene-2a,17 8-diol 17-acetate, melting atabout 147149. It displays an ultraviolet absorption maximum at about235.5 millirnicrons with a molecular extinction coefficient of 23,600and also infrared absorption peaks at about 2.85, 5.81 and 6.10 microns.

EXAMPLE 7 To a solution of 3.3 parts of 35,21-dihydroxy-pregn-5-en-20-one in 67.5 parts of tetrahydrofuran, in a nitrogen atmosphere, isadded, at approximately 15, 50 parts by volume of the approximately 1 Miodozinc-methylene reagent prepared as described in Example 1 and thehomogeneous mixture is allowed to stand at room temperature for about 24hours. At the end of that time nearly saturated aqueous ammoniumchloride is added and the organic solvent is removed by distillationunder reduced pressure. The solid which separates is collected byfiltration and is purified by crystallization from methylenechloride-hexane to afford pure 20-methylene-pregn- 5-ene-3,8,2l-diol,melting at about 186188. This compound exhibits infrared absorptionmaxima at about 3.12 and 6.12 microns.

EXAMPLE 8 To a solution of 9.9 parts of 21-hydroxypregn-4-ene-3,20-dione in 45 parts of tetrahydrofuran, in a nitrogen atmosphere, isadded at approximately 15, 200 parts by volume of an approximately 0.6 Miodozincmethylene reagent prepared as described in Example 1 and theresulting reaction mixture is stirred for about 24 hours. At the end ofthat time nearly saturated aqueous ammonium chloride is added carefullywith rapid stirring and the organic solvent is removed by distillationunder reduced pressure. The semi-solid residue is extracted into etherand the ether extract is washed successively with dilute aqueousammonium chloride and dilute aqueous potassium bicarbonate. Drying overanhydrous sodium sulfate followed by distillation of the solvent underreduced pressure affords an oily residue which is purified bychromatography on silica gel followed by elution with benzene andbenzene-ethyl acetate solutions to aiford the crude product. Furtherpurification is effected by crystallization of the eluted material frommethylene chloridehexane, thus affording pure2l-hydroxy-20-methylenepregn-4-en-3-one, melting at about 157-158. Anultraviolet absorption maximum is observed at about 242 millirnicronswith a molecular extinction coefiicient of 16,500 and infraredabsorption peaks are observed at about 2.97, 3.27, 6.02 and 6.20microns.

EXAMPLE 9 To a solution of 2.1 parts of 21-acetoxy-17a-hydroxypregn4'ene-3,11,20-trione in 25 parts of tetrahydrofuran is added 50parts by volume of an approximately 0.9 M iodozincmethylene reagentprepared as described in Example l and the resulting reaction mixture isstirred at room temperature for about 24 hours. At the end of that timenearly satuarted aqueous ammonium chloride is added and the organicsolvent is removed by distillation under reduced pressure. The residueis chromatographed on an alumina column, then eluted with 40% ethylacetate in benzene to yield pure21-acetoxy-17ahydroxy-20-methylenepregn-4-ene-3,1l-dione. This compoundexhibits an ultraviolet absorption maximum at about 238 millirnicronswith a molecular extinction coefiicient of about 17,600 and alsoinfrared absorption peaks at about 2.88, 5.71, 5.87, 6.05 and 6.19microns.

EXAMPLE 10 To a solution of 2 parts of17fi-acetoxy-2a-hydroxyandrost-4-en-3-one in 18 parts of tetrahydrofuranis added 30 parts by volume of approximately 0.9 M iodozincmethylenereagent prepared as described in Example 1 and the resulting reactionmixture is allowed to stand in a nitrogen atmosphere for about 20 hours.At the end of that time 50 parts of saturated ammonium chloride is addedand that mixture is stirred for about 30 minutes, then is extracted withether. The ether extract is washed successively with aqueous ammoniumchloride, water and aqueous potassium bicarbonate, then dried overanhydrous sodium sulfate and sttripped of solvent by distillation in anitrogen atmosphere. The solid crude product is purified byrecrystallization from aqueous methanol to afford pure3-methyleneandrost-4-ene-2a,17fi-diol 17- acetate, melting at about175-178". An ultraviolet absorption maximum is observed at about 238millirnicrons with a molecular extinction coefficient of about 22,000.Infrared absorption peaks are displayed at about 2.84, 3.23, 5.80 and6.08 microns.

EXAMPLE 11 To a solution of 19.2 parts of3B-benzyloxy-5a-hydroxypregnane-6,20-dione 20-ethylene ketal in 67.5parts of tetrahydrofuran is added 110 parts by volume of anapproximately 0.8 M iodozincmethylene reagent prepared as described inExample 1 and the reaction mixture is stirred at room temperature forabout 24 hours. 25% aqueous ammonium chloride in the amount of parts byvolume is then added cautiously and the resulting mixture is extractedwith ether. Removal of the ether by distillation under reduced pressureaffords an oily residue containing3,8-benzyloxy-5zx-hydroxy-6-methylenepregnan- 7 20-one 20-ethyleneketal. That material is dissolved in 80 parts of acetone, then is addedto a solution of 2 parts of concentrated hydrochloric acid in 20 partsof water. The resulting reaction mixture is stirred at room temperaturefor about 15 minutes, then is diluted with water. The precipitate thusformed is collected by filtration, dried and recrystallized frommethylene chloride-methanol to afford3fl-benzyloxy-5a-hydroxy-6-methylene-pregnan-20- one, melting at about180-183". Infrared absorption maxima are observed at about 2.87, 3.24,5.77 and 6.08 microns and nuclear magnetic resonance peaks at about 288and 294 cycles per second.

EXAMPLE 12 To a solution of 10.1 parts of 3fi,17fl-diacetoxy-5xhydroxyandrostan-6-one in 45 parts of tetrahydrofuran is added 70 partsby volume of approximately 0.8 M iodozincmethylene reagent prepared asdescribed in Example 1 and the resulting reaction mixture is stirred atroom temperature for about 3 hours. At that time 50 parts by volume of25% aqueous ammonium chloride is added cautiously and the resultingmixture is extracted with ether. The ether layer is separated, washedsuccessively with aqueous ammonium chloride and aqueous potassiumbicarbonate, then dried over anhydrous sodium sulfate. Removal of theether by distillation under nitrogen affords the crude product, which ispurified by recrystallization from methylene chloride-methanol, thusaffording pure 6-methyleneandrostane 318,50C 176 triol 3,17 diacetate,melting at about 219222. Infrared absorption maxima are observed atabout 2.90, 3.25, 5.78, 5.87 and 6.06 microns and nuclear magneticresonance peaksare observed at about 280 and 288 cycles per second.

EXAMPLE 13 To a solution of 1 part of 6-methylenandrostane-3/3,a,17B-triol 3,17-diacetate in 24 parts of methanol is added 5 parts byvolume of 45% aqueous potassium hydroxide and that mixture is allowed tostand in a nitrogen atmosphere at room temperature for about 16 hours.At the end of that time approximately 50 parts of water is added and theorganic solvent is removed by distillation under reduced pressure. Thesolid which crystallizes from the mixture is collected by filtration,then purified by recrystallization from ethyl acetate-ether to yield6-methylenandrostane-3[3,5a,17,8-triol melting at about 207-2085Infrared absorption maxima are observed at about 2.95, 3.23 and 6.07microns.

EXAMPLE 14 A mixture containing 5 parts of 6-methylenandrostane-3B,5a,l7B-tri0l 3,17-diacetate, 5 parts of acetic anhydride, 5 parts ofacetic acid, 0.15 part of p-toluenesulfonic acid and parts of dioxane isstirred at room temperature for about 16 hours, then is partiallyconcentrated under reduced pressure. Water is added to the residue andthe semi-solid product formed is collected by filtration and purified byrecrystallization from aqueous methanol to yield6-methylenandrostane-3{3,5a,17fl-triol 3,5,17-triacetate, melting atabout 116118. This compound exhibits infrared absorption maxima at about5.78 and 6.08 microns.

EXAMPLE The substitution of an equivalent quantity of 35,175-dipropionoxy-5u-hydroxyandrostan-6-one in the process of Example 12results in 6-methylenandrostane-3,3,5a,17B- triol 3,17-dipropionate.

When equivalent quantities of 6-methylenandrostane- 3fl,5oc,l.7fl-tri0l3,17-dipropionate, propionic anhydride and propionic acid aresubstituted in the procedure of Example 14, there is produced6-methylenandrostai1e-36, 50:,1713-tfl0l 3,5 l 7-tripropionate.

8 EXAMPLE 16 By substituting an equivalent quantity of l7a-acetoxy-21-hydroxypregn 4-ene-3,11,20-trione and otherwise proceeding accordingto the process of Example 2, there is obtained 17cc acetoxy 21hydroxy-ZO-methylenpregn-4- ene-3,11-dione.

EXAMPLE 17 The substitution of an equivalent quantity of ethylene glycoldimethyl ether for tetrahydrofuran in the procedure of Example 1 resultsin an approximately 1 M solution of the iodozincmethylene ethyleneglycol dimethyl ether reagent.

EXAMPLE 18 To a suspension of 45 parts of the reagent described inExample 2 with 360 parts of tetrahydrofuran is added, at l5, 22.5 partsof 3B,l7a-diacetoxy5a-hydroxypregnane-6,20-dione. Stirring at l5 iscontinued for about 15 minutes, at the end of which time the mixture isallowed to warm to room temperature. After the mixture has been stirredat room temperature for about 2 hours, a 1:1 mixture of acetic acid andwater is added cautiously. The resulting solution is concentrated toapproximately volume and about 300 parts of water is added. Theresulting solid is collected by filtration, washed with water, thenrecrystallized from aqueous methanol to afford 3,8, l7a-diacetoxy 5ahydroxy-6-methylenepregnan-20-one, melting at about -195". This compoundexhibits nuclear magnetic resonance peaks at about 37, 52, 123, 128, 284and 292 cycles per second.

What is claimed is:

1. The process which comprises contacting a reactive steriodal ketonewith a methylenating reagent prepared by contacting activated zinc witha methylene halide selected from the group consisting of methylenebromide and methylene iodide in tetrahydrofuran or an alkylene glycolether or a dialkoxyalkyl ether at elevated temperature to afford thecorresponding methylene steroid.

2. The process of claim 1 wherein the methylenating agent is thatprepared by contacting activated zinc with methylene bromide intetrahydrofuran at elevated temperature.

3. The process of claim 1 wherein the keto group of the reactivesteroidal ketone is activated by an adjacent hydroxy, acyloxy or oximinofunction.

4. The process of claim 1 wherein the keto group of the reactivesteroidal ketone is activated by an adjacent hydroxy function.

5. The process of claim 1 wherein the reactive steroidal ketone is asteroidal ketol of the following partial structural formula o: be

6. The process of claim 1 wherein the reactive steroidal ketone is asteroidal optionally acylated ketol of the following partial structuralformula wherein X is a hydroxy or acetoxy group and Y is hydrogen or ahydroxy or acetoxy group.

1 7. A compound of the formula 4 0000mm alkvl) OR 0H3 OH:

j 5 CH3 CH3 V l (lower alkyDCO I g V he i i 2 o 0 0 (lower alkyl) OR 10.As in claim 7, the compound which is 6-methylenewherein R, R and R" areselected from the group 0011- l I sisting of hydrogen and lower alkanoylradicals. AS 111 6131111 7, the compound Whlch 1S y 8. As in claim 7, acompound of the formula androstaneafifiw,17/3-tl'i01 3,17-diaC6tate- 12.As in claim 7, the compound which is 6-methylene- (IXJOGOWH yandrostane-3,8,5ot,17,8-triol 3,5,17-triacetate. CH3

References Cited UNITED STATES PATENTS 3,239,541 3/1966 Bowers et a1.260-3974 J 3,385,868 5/1968 Cross 260 -3974 LEWIS GOTTS, PrimaryExaminer E. G. LOVE, Assistant Examiner 6H U.S. c1. X.R. 9. As in claim7, a compound of the formula 260-397.4, 397.45, 397.47, 346.1, 429.9

0 3 (lower alkyl) 0 I I i l l UNTTED STATES PATENT QTFEE QETTT'TCATE T@QREQTTN Patent 39 Dated January 11, Inventor(s) Leonard N. Nysted It iscertified that error appears in the aboveidentified patent and that saidLetters Patent are hereby corrected as shown below:

Column 5, line 68, "tempreature" should be temperature Column t, line4]., "iodozinicmethylene" should be iodozincmethylene Column 5, line &6,"benzeneethyl" should be benzene-ethyl Column 6, line 51, "satuarted"should be saturated Column 6, line 5 "sttripped" should be strippedColumn 7, line 29, methyleneandrosbane" should be methylenandrostanee UColumn 10, formula 0 should be I s CH 000(lower alkyl) 0 H (lower alkyUOCO(lower alkyl) Signed and sealed this With day of July I 972.

(SEAL) Attest:

EDWARD M.,F'LETCHER,JR. ROBERT GOTTSGHALK Attesting Officer Commissionerof Patents FORM PO-105O (10-69) USCOMM-DC 60376-P69 9 U5. GOVERNMENTPRINTING OFFICE: 1969 O-36633A

